Traumatic brain injury (TBI) is a major cause of premature death and disability worldwide. No therapy has been effective in reducing mortality and improving functional outcomes. We recently completed an NINDS-funded, Phase I/IIa double-blinded, randomized placebo-controlled pilot clinical trial examining the pharmacokinetics, safety, and activity of progesterone, a steroid found to have powerful neuroprotective properties in multiple different animal models of brain injury. Based on the extensive preclinical evidence of activity and the promising findings of our pilot study we propose to conduct a phase III clinical trial to definitively assess the efficacy of this treatment for adults with moderate to severe acute TBI. Our primary objective is to determine the effect of administering intravenous progesterone (initiated within 4 hours of injury and administered for 72 hours, followed by an additional 24 hour taper) versus placebo for treating victims of moderate to severe (GCS 12-4) TBI. Our secondary objectives are to examine the effects of progesterone vs. placebo in patients with moderate to severe TBI on 6 month mortality, Disability Rating Scale score, cognitive, neurological and functional outcome using a select battery of tests, and the rates of adverse and severe adverse events. If the therapeutic benefits observed in animals and from our pilot study are replicated, administration of intravenous progesterone should decrease mortality and improve neurological function. Positive results would represent a major advance in the treatment of TBI.